This invention relates to the field of pharmaceutical administration. More particularly, the invention relates to compositions and methods for the administration of pharmaceutically active substances by permeation of mucosal surfaces of the body such as the mucosal linings of the nasal cavity or the bronchopulmonary system.
The mode of administration of a pharmaceutical product can have a very significant effect on the bioavailability and pharmacokinetics of the product. Furthermore, the mode of administration can have a significant effect on patient compliance inasmuch as patients are more likely to comply with medication regimens when the mode of administration is convenient and comfortable. The effect of the mode of administration on patient compliance is particularly strong where the patient must self-administer the drug on a chronic basis, e.g. in the case of insulin.
In terms of convenience and comfort, oral administration is generally the most preferred method. Unfortunately, many drugs cannot be administered orally due to extensive degradation of the drug which occurs in the gastrointestinal tract before the drug is transferred into the general circulation. Protein and polypeptide drugs are particularly prone to being degraded in the gastrointestinal tract by various hydrolytic and enzymatic means. Accordingly, protein and polypeptide drugs are generally not orally administrable.
The advent of recombinant DNA technology in recent years has made it possible to produce on a commercial scale virtually any polypeptide or protein whose structure has been elucidated. These include a multitude of substances which have great potential pharmaceutical value, but which were previously available from natural sources only in minute quantities suitable solely for research purposes Now that these protein and polypeptide drugs can be produced on a commercial scale, the inability to administer them in a convenient and comfortable manner is one of the few barriers to their becoming staple items of the pharmaceutical armamentarium for fighting or preventing disease. Until fairly recently, the only broadly applicable means for delivering protein or peptide drugs were the parenteral routes.
The aerosol administration of insulin to animals and humans via the respiratory system has been reported by several groups (Ayer, A. A., Antiseptic, 51, 1161 [1954]; Govinda-Rao, A. R., Indian J. Physiol. Pharmacol., 3, 161 [1959]; Wigley, F. M. et al., Diabetes, 20, 552 [1971]; Yalow, R. S. and Berson, S. A., Methods Biochem. Anal., 12, 69 [1968]). Shih-Wei Lee and John J. Sciarra reported the preparation of aerosol dosage forms containing insulin, fluorocarbon propellant and oleyl alcohol (to improve insulin suspension), however, no bioavailability results were given (J. Pharm. Sci., 65, No. 4, 567 [1976]). Unfortunately, due to the low level of bioavailability of aerosol-administered insulin, these delivery systems have not come into therapeutic use.
Recently, Martin Carey and coworkers developed a system for delivering drugs, particularly proteins and polypeptides, by intranasal or other transmucosal routes using low toxicity permeation enhancers of the amphiphilic steroid family, e.g. fusidic acid derivatives to promote efficient transport of the drug across the mucosal surface (U.S. Pat. Nos. 4,548,922 and 4,746,508). The disclosed compositions, which are generally water-based, have been demonstrated to be useful for the intranasal delivery in humans and animals of a variety or proteins and peptides, including insulin, human growth hormone, salmon calcitonin, histerelin (an analogue of luteinizing hormone releasing hormone) and .beta.-endorphin.
In the aqueous composition of Carey et al. the fusidic acid derivative is present at a concentration above its critical micellar concentration. It is believed that the fusidic acid derivative forms micelles containing the drug and that these micelles are the entities which provide for penetration of the drug through the mucosa.
In some subjects, the fusidic acid derivative employed in the method of Carey et al. has exhibited mild irritation of the nasal tissues. The irritation is relatively mild by comparison with the discomfort associated with drug delivery by injection and varies considerably in degree from subject to subject. Furthermore, the irritation does not appear to be associated with significant, nontransient effects on the integrity of the intranasal mucosa. Nonetheless, it would be highly desirable to provide a composition for transmucosal drug delivery having the efficacy exhibited by the system of Carey et al., but without the concomitant irritation experienced by some subjects.
Another drawback associated with the compositions of Carey et al., as well as other systems for delivering proteins and polypeptides, is that they are, for the most part, aqueous systems. Unfortunately, proteins and polypeptides generally have limited stability in aqueous systems. Thus, it is necessary either to use the composition shortly after it is prepared or to provide the protein or peptide drug in lyophilized form for aqueous reconstitution at the time of use. Reconstitution of the composition is inconvenient and introduces the opportunity for errors in formulation or for the introduction of contaminants.
Another problem associated with intranasal delivery using aqueous systems results from the fact that they are usually applied by an applicator which provides mechanical pumping means for pumping the aqueous composition through a spray nozzle. The resulting spray pattern can vary considerably among individual users and from application to application, thus causing difficulty in controlling dosage.
It is an object of the present invention to provide compositions and methods for effectively administering pharmaceutically active substances, particularly protein or polypeptide drugs, across mucosal surfaces, without the mild irritation sometimes associated wIth prior art transmucosal delivery systems.
It is a further object of the invention to provide compositions and methods for administration of pharmaceutically active substances, particularly proteins or polypeptides, wherein the compositions have longer stability than aqueous compositions of the prior art and do not require reconstitution at the time of use.
It is yet a further object of the invention to provide compositions and methods for transmucosal delivery of pharmaceutically active substances which allow delivery of uniform dosage from subject-to-subject and application-to-application.
Other objects and advantages of the invention will become readily apparent from the disclosure which follows.